Submissions for variant NM_007294.4(BRCA1):c.1065G>A (p.Lys355=)

gnomAD frequency: 0.00011  dbSNP: rs41286292

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111537	SCV000578264	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084435	SCV000075337	benign	Hereditary breast ovarian cancer syndrome	2024-01-13	criteria provided, single submitter	clinical testing
Counsyl	RCV000111537	SCV000154014	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-01-23	criteria provided, single submitter	literature only
GeneDx	RCV000159867	SCV000209920	benign	not specified	2014-10-01	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000163137	SCV000213652	likely benign	Hereditary cancer-predisposing syndrome	2014-09-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000163137	SCV000682932	benign	Hereditary cancer-predisposing syndrome	2015-12-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586457	SCV000698829	benign	not provided	2016-10-05	criteria provided, single submitter	clinical testing	Variant summary:The BRCA1 c.1065G>A (p.Lys355Lys) variant causes a synonymous change involving a non-conserved nucleotide with 5/5 splicing algorithms predict no significant effect on splice donor and acceptor sites, which is consistent with an in vitro study (Anczukow et al 2008) showing that the variant did not affect splicing based on a mini-gene assay. This variant was found in 23/121396 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0003297 (22/66736). This frequency is lower than the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005), but suggests that it may be a rare polymorphism. In at least two reported patients (1 published and 1 unpublished finding from UMD), this variant co-occurred with another deleterious variant in BRCA1, strongly supporting a benign outcome. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, all evidence supports a non-pathogenic nature for the variant, and the variant was classified as benign.
Sema4, Sema4	RCV000163137	SCV002537991	likely benign	Hereditary cancer-predisposing syndrome	2021-06-16	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735494	SCV003838250	likely benign	Breast and/or ovarian cancer	2022-05-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000586457	SCV004009799	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	BRCA1: BP4, BP7
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000111537	SCV004016780	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-07	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV001084435	SCV004228112	likely benign	Hereditary breast ovarian cancer syndrome	2023-09-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000111537	SCV004818377	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2024-01-11	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111537	SCV000143994	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2000-08-09	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354009	SCV000591314	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Lys355Lys variant was identified in 2 of 4244 proband chromosomes (frequency: 0.000) from individuals or families with hereditary breast and ovarian cancer (Borg 2010, Ricevuto 2001). The variant was also identified in dbSNP (ID: rs41286292) “With other allele”, with a minor allele frequency of 0.0002 (1000 Genomes Project), Exome Variant Server project in 1 of 8599 European American alleles, the ClinVar database 4X (classified as benign (BIC and GeneDx), likely benign (Counsyl) and uncertain significance (Invitae)), GeneInsight VariantWire database (2X, classified as “predicted unlikely impact” by a clinical laboratory), the BIC database (2X with no clinical importance), and UMD (17X as an unknown variant). In UMD the variant was identified with a co-occurring pathogenic BRCA1 variant (p.Val939LeufsX61), increasing the likelihood that the p.Lys355Lys variant does not have clinical significance. The variant was also identified by the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 22 of 66736 chromosomes (frequency: 0.0003297) from a population of European (Non-Finnish) individuals, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The variant was also identified by our laboratory in 2 individuals with breast cancer. The p.Lys355Lys variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
MVZ Praenatalmedizin und Genetik Nuernberg	RCV000111537	SCV000777896	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2018-05-01	no assertion criteria provided	clinical testing	This rare variant (gnomAD) was found multiple times in databases to be classified as uncertain or likely benign. Interestingly we found this variant in a patient who harbored also a pathogenic BRCA2-variant (NM_000059.3|c.1813dupA|het). Therefore we rate this variant as likely benign.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735494	SCV000863632	benign	Breast and/or ovarian cancer	2012-06-19	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000586457	SCV001905679	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000586457	SCV001927852	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000586457	SCV001951704	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000586457	SCV001965871	likely benign	not provided		no assertion criteria provided	clinical testing